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In an early-phase study involving 17 patients with highly refractory multiple myeloma, CAR T-cell therapy with specificity for a G protein–coupled receptor that is expressed on myeloma cells produced a response in 71% of the patients.

The Endothelial Activation and Stress Index (EASIX) is a prognostic tool that uses common clinical laboratory values and has been shown to predict non-relapse mortality (NRM) and overall survival (OS) at the onset of acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). We hypothesized that EASIX calculated at different time points pre- and post- HCT may predict NRM and OS, and that EASIX calculated at onset of GVHD may predict response to steroids. We evaluated the EASIX score pre- and post-HCT in 152 patients with lymphoid malignancies undergoing unmodified reduced intensity conditioning (RIC) alloHCT with uniform GVHD prophylaxis. In multivariate analysis, EASIX calculated pre-HCT was significantly associated with higher NRM (HR = 1.64, p = 0.009) and lower OS (HR = 1.33, p = 0.046). Furthermore, EASIX calculated at day 30 and at day 100 was associated with increased NRM (HR = 1.65, p < 0.001; and HR = 1.65, p < 0.001) and decreased OS (HR = 1.27, p = 0.018; and HR = 1.49, p < 0.001), independent of HCT-CI, disease and conditioning regimen. Our study shows that high EASIX scores at various time points pre- and post-HCT are significantly associated with poorer overall outcomes. EASIX provides an independent and easily accessible tool to predict outcomes that can be complementary to other measures of risk stratification for patients undergoing HCT.

Abstract Rationale Pulmonary complications (PCs) cause significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HCT). Shifts in gut microbiota have been linked to HCT outcomes; however, their effect on PCs is unknown. Objectives To investigate whether changes in gut microbiota are associated with PCs after HCT. Methods A single-center observational study was performed on 94 patients who underwent HCT from 2009 to 2011 and who were previously enrolled in a protocol for 16S ribosomal RNA sequencing of fecal microbiota. The primary endpoint, PC, was defined by new abnormal parenchymal findings on chest imaging in the setting of respiratory signs and/or symptoms. Outcomes were collected up to 40 months after transplant. Clinical and microbiota risk factors for PCs and mortality were evaluated using survival analysis. Measurements and Main Results One hundred twelve PCs occurred in 66 (70.2%) subjects. A high comorbidity index (hazard ratio [HR], 2.30; 95% confidence interval [CI], 1.30–4.00; P = 0.004), fluoroquinolones (HR, 2.29, 95% CI, 1.32–3.98; P = 0.003), low baseline diversity (HR, 2.63; 95% CI, 1.22–5.32; P = 0.015), and γ-proteobacteria domination of fecal microbiota (HR, 2.64; 95% CI, 1.10–5.65; P = 0.031), which included common respiratory pathogens, predicted PCs. In separate analyses, low baseline diversity was associated with PCs that occurred preengraftment (HR, 6.30; 95% CI, 1.42–31.80; P = 0.016), whereas γ-proteobacteria domination predicted PCs postengraftment (HR, 3.68; 95% CI, 1.49–8.21; P = 0.006) and overall mortality (HR, 3.52; 95% CI, 1.28–9.21; P = 0.016). Postengraftment PCs were also independent predictors of death (HR, 2.50; 95% CI, 1.25–5.22; P = 0.009). Conclusions This is the first study to demonstrate prospective changes in gut microbiota associated with PCs after HCT. Postengraftment PCs and γ-proteobacteria domination were predictive of mortality. This suggests an adverse relationship between the graft and lung, which is perhaps mediated by bacterial composition in the gut. Further study is warranted.

Malignant T-cell transformation after chimeric antigen receptor (CAR) T-cell therapy has been described, but the contribution of CAR integration to oncogenesis is not clear. Here we report a case of a T-cell lymphoma harboring a lentiviral integration in a known tumor suppressor, TP53 , which developed in a patient with multiple myeloma after B-cell maturation antigen (BCMA) CAR T-cell therapy. A woman with multiply relapsed multiple myeloma had complete remission with cilta-cel, but a low-grade T-cell lymphoma soon developed in the GI tract that contained an insertion of the CAR construct disrupting expression of p53.

BACKGROUNDUnderstanding outcomes and immunologic characteristics of cellular therapy recipients with SARS-CoV-2 is critical to performing these potentially life-saving therapies in the COVID-19 era. In this study of recipients of allogeneic (Allo) and autologous (Auto) hematopoietic cell transplant and CD19-directed chimeric antigen receptor T cell (CAR T) therapy at Memorial Sloan Kettering Cancer Center, we aimed to identify clinical variables associated with COVID-19 severity and assess lymphocyte populations.METHODSWe retrospectively investigated patients diagnosed between March 15, 2020, and May 7, 2020. In a subset of patients, lymphocyte immunophenotyping, quantitative real-time PCR from nasopharyngeal swabs, and SARS-CoV-2 antibody status were available.RESULTSWe identified 77 patients with SARS-CoV-2 who were recipients of cellular therapy (Allo, 35; Auto, 37; CAR T, 5; median time from cellular therapy, 782 days; IQR, 354-1611 days). Overall survival at 30 days was 78%. Clinical variables significantly associated with the composite endpoint of nonrebreather or higher oxygen requirement and death (n events = 25 of 77) included number of comorbidities (HR 5.41, P = 0.004), infiltrates (HR 3.08, P = 0.032), and neutropenia (HR 1.15, P = 0.04). Worsening graft-versus-host disease was not identified among Allo recipients. Immune profiling revealed reductions and rapid recovery in lymphocyte populations across lymphocyte subsets. Antibody responses were seen in a subset of patients.CONCLUSIONIn this series of Allo, Auto, and CAR T recipients, we report overall favorable clinical outcomes for patients with COVID-19 without active malignancy and provide preliminary insights into the lymphocyte populations that are key for the antiviral response and immune reconstitution.FUNDINGNIH grant P01 CA23766 and NIH/National Cancer Institute grant P30 CA008748.

Gemtuzumab ozogamicin (GO), a humanized anti-CD33 monoclonal antibody conjugated to the cytotoxic antibiotic agent calicheamicin, is approved for the treatment of newly-diagnosed CD33 + AML in adults and children ≥ 1 month old, and relapsed or refractory CD33 + AML in adults and children ≥ 2 years old. GO treatment has been associated with an increased risk of hepatotoxicity and hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), especially following hematopoietic stem cell transplantation. Other non-specific serious adverse events (SAEs) associated with GO treatment are myelosuppression, bleeding/thrombocytopenia, infusion-related reaction, and tumor lysis syndrome. This report summarizes an expert panel of physicians’ recommendations for the evaluation and management of SAEs following GO, emphasizing the prevention and management of VOD/SOS.

A wide variety of new therapeutic options for Multiple Myeloma (MM) have recently become available, extending progression-free and overall survival for patients in meaningful ways. However, these treatments are not curative, and patients eventually relapse, necessitating decisions on the appropriate choice of treatment(s) for the next phase of the disease. Additionally, an important subset of MM patients will prove to be refractory to the majority of the available treatments, requiring selection of effective therapies from the remaining options. Immunomodulatory agents (IMiDs), proteasome inhibitors, monoclonal antibodies, and alkylating agents are the major classes of MM therapies, with several options in each class. Patients who are refractory to one agent in a class may be responsive to a related compound or to a drug from a different class. However, rules for selection of alternative treatments in these situations are somewhat empirical and later phase clinical trials to inform those choices are ongoing. To address these issues the NCI Multiple Myeloma Steering Committee formed a relapsed/refractory working group to review optimal treatment choices, timing, and sequencing and provide recommendations. Additional issues considered include the role of salvage autologous stem cell transplantation, risk stratification, targeted approaches for genetic subsets of MM, appropriate clinical trial endpoints, and promising investigational agents. This report summarizes the deliberations of the working group and suggests potential avenues of research to improve the precision, timing, and durability of treatments for Myeloma.

Disease progression is a substantial challenge in patients with non-Hodgkin lymphoma (NHL) undergoing chimeric antigen receptor T cell (CAR-T) therapy. Here we present InflaMix (INFLAmmation MIXture Model), an unsupervised quantitative model integrating 14 pre-CAR-T infusion laboratory and cytokine measures capturing inflammation and end-organ function. Developed using a cohort of 149 patients with NHL, InflaMix revealed an inflammatory signature associated with a high risk of CAR-T treatment failure, including increased hazard of death or relapse (hazard ratio, 2.98; 95% confidence interval, 1.60–4.91; P  < 0.001). Three independent cohorts comprising 688 patients with NHL from diverse treatment centers were used to validate our approach. InflaMix consistently and reproducibly identified patients with a higher likelihood of disease relapse and mortality, and it provided supplementary predictive value beyond established prognostic markers, including tumor burden. Moreover, InflaMix exhibited robust performance in cases with missing data, maintaining accuracy when considering only six readily available laboratory measures. These findings show that InflaMix is a valuable tool for point-of-care clinical decision-making in patients with NHL undergoing CAR-T therapy. A preinfusion circulatory inflammation biomarker-based signature predicts the likelihood of treatment failure in patients with non-Hodgkin lymphoma who were treated with CAR-T cell therapy, with an inflammatory cluster assignment being prognostic of clinical response and survival outcomes.

Background and Objectives High-dose melphalan is an integral part of conditioning chemotherapy prior to both autologous and allogeneic hematopoietic cell transplantation. While underexposure may lead to relapse, overexposure may lead to toxicities include mucositis, diarrhea, bone marrow suppression, and rarely sinusoidal obstruction syndrome. In this study, we describe the population pharmacokinetics of high-dose melphalan as a first step towards individualized dosing. Methods Melphalan samples were collected in patients receiving an allogeneic or autologous hematopoietic cell transplantation between August 2016 and August 2020 at the Memorial Sloan Kettering Cancer Center. A population-pharmacokinetic model was developed using NONMEM. Results Based on a total of 3418 samples from 452 patients receiving a median cumulative dose of 140 mg/m 2 , a two-compartment population-pharmacokinetic model was developed. Fat-free mass was a covariate for clearance, central volume of distribution, and inter-compartmental clearance, while glomerular filtration rate predicted clearance. Simulation studies showed that based on fixed body surface area-based dosing, renal impairment has a higher impact in increasing melphalan exposure compared with obesity. Conclusions The proposed model adequately describes the population pharmacokinetics of melphalan in adult patients receiving a hematopoietic cell transplantation. This model can be used to define the therapeutic window of melphalan, and subsequently to develop individualized dosing regimens aiming for that therapeutic window in all patients.